Exclusion of CLIC5 as a Candidate Gene and Identification of NEFM as a Possible Novel Gene Correlated With Autosomal Recessive Pure Cerebellar Ataxia in a Highly Consanguineous Family

Background Pure cerebellar ataxia is a neurological disorder characterised by isolated cerebellar dysfunction, arising from either developmental anomalies or progressive degenerative processes. Precise genetic diagnosis remains challenging. Methods The aim of this study was to use a whole‐exome sequencing approach to study a large, highly consanguineous Italian family in order to identify a new gene correlated with pure cerebellar ataxia. Results Sequencing excluded the presence of mutations in known‐related genes but revealed a homozygous missense variant in CLIC5 ; however in vivo analysis of a CLIC5 KO mouse model showed vestibular dysfunction without cerebellar involvement, suggesting that CLIC5 is not directly involved in pure cerebellar ataxia onset. Further analysis identified two compound heterozygous variants in NEFM , and in silico analysis showed that they dysregulate NEFM phosphorylation. Phosphorylation of neurofilaments and subsequent formation of aggregates has already been linked to conditions such as ageffing and neurodegeneration. Moreover, in vivo studies on mice transgenic for human NEFM have correlated NEFM phosphorylation and aggregation with neurodegeneration. Finally, neurofilaments have been proposed to be correlated to ataxia and autoimmune cerebellar ataxia. Conclusion We therefore propose NEFM as a possible new candidate gene for hereditary cerebellar ataxia. These findings could be useful for advancing the genetic diagnosis of hereditary pure cerebellar ataxia, possibly enabling the screening of healthy carriers.